CPN (Section Chief: Lorenzo Leggio, M.D., Ph.D., M.Sc.) Joint NIAAA-NIDA Annual Report 2017 The joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical inpatient and outpatient studies in order to identify possible novel medications for addiction. Under the leadership of Lorenzo Leggio, M.D., Ph.D., M.Sc., the CPN team is particularly interested in the role of the gut-liver-brain axis in alcohol-seeking behaviors. Both preclinical and human approaches are in progress or under development in order to shed light on the possible role of the gut-liver-brain axis in alcohol use disorder (AUD). Animal experiments demonstrate that central ghrelin administration not only stimulates reward processing but is also required for stimulation of that system by alcohol (Jerlhag et al., 2009; Suchankova et al., 2013). Human studies show a positive correlation between ghrelin concentrations and alcohol craving scores, and intravenous ghrelin acutely increases alcohol craving in individuals suffering with AUD. Together, preclinical and clinical studies suggest that ghrelin might represent a novel pharmacological target for treatment (reviewed in: Leggio, 2010). A within-subject, double-blind, placebo-controlled human laboratory study (protocol 13-AA-0043) was developed by the CPN Section to investigate whether IV ghrelin, as compared to placebo, increases motivation for alcohol reward, as measured by a progressive ratio schedule paradigm with IV alcohol self-infusion; and whether IV ghrelin, as compared to placebo, will increase the BOLD activation in the ventral striatum during an fMRI session. Data were analyzed and a paper is currently under review (Farokhnia et al. under review). Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use as never been tested in humans. In order to test this hypothesis, the CPN Section developed a translational project to assess the role of a GHS-R1a antagonist manufactured by Pfizer as a novel medication for AUD. This project was developed in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from the University of Rhode Island and was recently awarded with a NCATS grant award (UH2/UH3 TR000963) to partially support this project. This project is conducted at the NIH Intramural Research Program under Dr. Leggios leadership; pharmacokinetics (PK)/pharmacodynamic (PD) investigations are conducted in Dr. Akhlaghis lab. A Phase 1b clinical study (protocol 14-AA-0042) was completed and a Phase 2a clinical study (protocol 16-AA-0080) was recently started. Recent research suggests that oxytocin (OT) may play a role in the neurobiology of AUD. In animals, OT administration produces long-term decreases in alcohol reinforcement, decreases alcohol seeking during abstinence, attenuates drug tolerance, and decreases withdrawal symptoms (reviewed in Lee et al. 2016). Mary Lee, M.D., Staff Clinician in Dr. Leggios CPN Section, was awarded an NIH B2B grant award (2014-2015) to partially support this project. Preclinical work in collaboration with NIDA (Marilyn Huestis, M.D.) and NIMH (Bruno Averbeck, Ph.D.) basic scientists demonstrated that peripherally administered OT crosses the blood brain barrier and is detectable in the central spinal fluid (Lee et al. Molecular Psychiatry 2016). Additional preclinical work with rodents and monkeys is under way. Furthermore, a clinical study developed by the CPN Section (protocol 16-AA-0082) is planned to start soon. Increasing evidence suggests a role of the gut microbiota in neuropsychiatric disorders. In particular, clinical and translational research has suggested a causality link between the gut microbiota and symptoms of anxiety, depression and autism (reviewed in: Dinan and Cryan, 2016). A recent study suggests that changes in the gut microbiota in patients with AUD and increased gut permeability correlate with alcohol craving. However, the small sample size and the retrospective and self-reported nature of some of the assessments limit the interpretation of these findings. A recent systematic review conducted by our team, (Temko, Bouhlal et al. Alcohol and Alcoholism 2017) indicates that the understanding of the role of the gut microbiota in AUD is very limited and deserves additional investigation. Therefore, the CPN Section developed a translational and clinical project to investigate the role of the gut microbiota in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. This clinical study (17-AA-0093) was recently approved by the IRB. We have also conducted preliminary work studying the mineralcorticoid hormone aldosterone and its mineralcorticoid receptor (MR) in three differences species, using a monkey model of excessive alcohol use (collaboration with Dr. Katheleen Grant), a rat model of alcohol dependence (collaboration with Leandro Vendruscolo, Ph.D., George Koob, Ph.D., and Markus Heilig, M.D., Ph.D.) and in alcohol-dependent patients (collaboration with Giovanni Addolorato, M.D.). We found that aldosterone concentrations increased over time in non-human primates that self-administered alcohol daily for 6-12 months. We also found that the lower was the expression of the MR gene in their amygdala, the higher was their alcohol drinking. When we looked at the amygdala of dependent rats, we found similar results. Additionally, the lower was the expression of the MR gene in the rat amygdala, the higher was their anxiety-like behavior (in addition to alcohol drinking). Finally, in alcohol-dependent patients, we found that those patients with higher blood concentrations of aldosterone also had higher craving for alcohol, higher anxiety and consumed more alcohol. These results were recently published: Aoun et al. Molecular Psychiatry 2017). Baclofen has been identified as a possible medication able to reduce alcohol craving and intake in alcohol dependent individuals. Preclinical and clinical studies indicated that baclofen is effective in reducing alcohol craving and intake. However, some studies found a robust treatment effect, but no differences between baclofen and placebo (e.g., Garbutt et al., 2010). This discrepancy suggests that individuals with AUD may respond differently to baclofen, e.g., patients with higher levels of anxiety may respond better to baclofen (Leggio et al., 2010). Thus, the CPN Section developed a clinical protocol (13-AA-0040) to test the role of baclofen on alcohol-related outcomes in alcoholic individuals with high anxiety levels. The design was a between-subject randomized double-blind controlled study with the medication conditions as the between-subjects factor. Dr. Leggio received a NARSAD Award from the Brain and Behavior Research Foundation to partially support this study. Study results show that baclofen does not reduce alcohol craving or self-administration but it does affect the subjective effects of alcohol, suggesting that baclofens mechanism of action in AUD may take place as a substitution therapy. Results were published: Farokhnia et al. Translational Psychiatry 2017.